Chemo-enzymatic Synthesis of Structurally Complex Sorbicillin-Derived Natural Products and Non-Natural Analogd

在过去的几年里，我们小组使用SorbC首次开发了索比西林类天然产物的化学-酶促合成，使几乎所有（杂）二聚体和简单杂合化合物的高度区域选择性和立体选择性成为可能，因此对它们的合成可用性做出了重要贡献。虽然这些合成路线比以前的纯化学全合成明显更快和更有效，但仍然存在一些限制：在传统的间歇方法中，山梨西林向山梨西林醇的转化通常不完全，并且在所有合成中观察到不希望的二聚体副产物的形成，这不仅导致有时需要苛刻的色谱纯化，而且重要的是，无论具体的目标结构如何，最大产率都在30%（± 5%）左右。这是可以接受的所有目标化合物处理到目前为止，直接在原位生成后，氧化生产的山梨西林醇。然而，这些限制对于所需的后续多阶段合成转化为甚至更复杂的代表物是有问题的，以及对于通过山梨西林醇与高度官能化的反应配偶体的反应形成的物质是有问题的，所述高度官能化的反应配偶体不能简单地大量过量使用。这特别适用于生产大量物质以进行详细的生物学表征和化合物的衍生化，例如优化生物活性或安装分子探针以阐明作用机制。本研究项目将有针对性地解决这些问题，应用所开发的方法学，建立第一个立体选择性全合成复杂的索比西林类化合物，从而为广泛的生物医学和机理后续研究奠定基础。具体而言，我们计划：·SorbC的固定化和在流动反应器中连续实施氧化脱芳构化，随后通过适当的反应控制形成高选择性产物·开发了从与复杂的亲二烯体的Diels-Alder环加成反应或多阶段后续化学反应的混合山梨西林类化合物的第一立体选择性合成·首次通过迈克尔加成反应和多阶段后续化学反应立体选择性全合成杂合山梨西林类化合物·初步工作旨在阐明分子作用模式，最初以抗生素Rezishanon A为例，

The development of the first chemo-enzymatic syntheses of sorbicillinoid natural products using SorbC in our group over the last few years has enabled highly regio- and stereoselective access to almost all (hetero-)dimeric and simple hybrid compounds of this class and has thus made an important contribution to their synthetic availability. While these synthetic routes are significantly faster and more efficient than previous, purely chemical total syntheses, some limitations remain: the usually incomplete conversion of sorbicillin to sorbicillinol in classical batch processes, combined with the formation of undesired dimeric by-products observed in all syntheses, not only leads to the need for sometimes demanding chromatographic purifications, but importantly also to maximum yields of around 30% ( ± 5%), regardless of the specific target structure. This was acceptable for all target compounds tackled so far, which are generated directly in situ after the oxidative production of sorbicillinol. However, these limitations are problematic for required subsequent multi-stage synthetic transformations to even more complex representatives, as well es for substances that are formed via a reaction of sorbicillinol with highly functionalized reaction partners that cannot simply be used in large excess. This applies in particular to the production of larger amounts of substances for detailed biological characterization and to the derivatization of the compounds, e.g. to optimize biological activities or to install molecular probes to elucidate mechanisms of action. In this research project, we will solve these problems in a targeted manner, apply the developed methodology to establish the first stereoselective total syntheses of complex sorbicillinoids and thus lay the foundation for extensive biomedical and mechanistic follow-up investigations. Specifically, we are planning: • Immobilization of SorbC and continuous implementation of the oxidative dearomatization in flow reactors with subsequent highly selective product formation through suitable reaction control • Development of the first stereoselective synthesis of hybrid sorbicillinoids from Diels-Alder cycloaddition reactions with complex dienophiles or with multi-stage subsequent chemistry • Development of first stereoselective total syntheses of hybrid sorbicillinoids from Michael addition reactions with multi-stage subsequent chemistry • Initial work to towards elucidation of molecular modes of action, initially using the example of the antibiotic Rezishanon A